Antimalarial drug resistance—is it time to re-evaluate Plasmodium falciparum orthologous genes?
Authors: Aamer Ali Khattak, Usman Ayub Awan, Muhammad Faisal Nadeem, Adnan Yaqoob, Shehrish Kamran
Journal: The Lancet Microbe (2022)

The COVID-19 pandemic has wreaked havoc on malaria prevention, diagnosis, and treatment, resulting in 241 million malaria cases and 627 000 malaria deaths globally in 2020, up from 14 million malaria cases in 2019, and the disruption was estimated to have contributed to 47 000 malaria deaths, two-thirds of the 2019–20 increase.1WHOWorld malaria report 2021.https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021Date: 2021Date accessed: March 30, 2022Google Scholar Malaria caused by Plasmodium vivax has the potential to affect 2·5 billion people globally, accounting for 88% of people at risk of malaria overall; however, due to its more severe course, Plasmodium falciparum receives the most attention.2Howes RE Battle KE Mendis KN et al.Global epidemiology of Plasmodium vivax.Am J Trop Med Hyg. 2016; 95: 15-34Crossref PubMed Scopus (224) Google Scholar Despite the fact that P vivax has a benign malaria course, occasional occurrences of this species’ malignant pattern have been observed worldwide.3Phyo AP Dahal P Mayxay M Ashley EA Clinical impact of vivax malaria: a collection review.PLoS Med. 2022; 19e1003890Crossref PubMed Scopus (7) Google Scholar, 4Kojom Foko LP Arya A Sharma A Singh V Epidemiology and clinical outcomes of severe Plasmodium vivax malaria in India.J Infect. 2021; 82: 231-246Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Antimalarial drug resistance is on the rise, and its spread is one of the most serious risks to malaria control and eradication. In P vivax and P falciparum, resistance to antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, and atovaquone has already been established.5Tseha ST Plasmodium species and drug resistance. IntechOpen, London2021Google Scholar Antimalarial drug resistance mechanisms and key molecular markers in P falciparum have been well described in vitro and in vivo; nevertheless, these mechanisms are difficult to assess in P vivax due to the absence of a cultivation system for this species.6Asih PBS Syafruddin D Plasmodium vivax and Drug Resistance.in: Tyagi RK Plasmodium species and drug resistance. IntechOpen, London2021https://doi.org/10.5772/intechopen.97320Date: 2021Crossref Google ScholarThe search for antimalarial resistance in P vivax has centred on P falciparum orthologous genes (multidrug resistance, chloroquine resistance transporter, dihydropteroate synthase, and dihydrofolate reductase) being strongly (though not completely) associated to ex-vivo resistance assay outputs and in-vivo treatment failure.7Buyon LE Elsworth B Duraisingh MT The molecular basis of antimalarial drug resistance in Plasmodium vivax.Int J Parasitol Drugs Drug Resist. 2021; 16: 23-37Crossref PubMed Scopus (14) Google Scholar P vivax does not have a reliable genetic marker for drug resistance, probably because the drug resistance phenotype is reliant on multiple convergent molecular processes for the same outcome. It is necessary to narrow down the number of polymorphisms to be able to validate resistance markers to a drug sensitivity phenotype. Unfortunately, attempts to prove genotypic resistance have failed so far due to a unavailability of continuous culturing in P vivax, which is essential to achieve a measurable, accurate phenotypic consequence. P vivax has only tentatively been associated with treatment failure despite a quantitative increase in gene expression. Consequently, there are not any clear guidelines for determining whether in-vitro responses are sensitive or resistant to antimalarials.8Ferreira MU Nobrega de Sousa T Rangel GW et al.Monitoring Plasmodium vivax resistance to antimalarials: persisting challenges and future directions.Int J Parasitol Drugs Drug Resist. 2021; 15: 9-24Crossref PubMed Scopus (13) Google ScholarAlthough molecular approaches are not the most efficient means to monitor P vivax treatment susceptibility, they might be a good starting point. Herein, retrospective research on mutations of well-characterised molecular markers subject to prolonged antimalarial drug pressure is possible. The most difficult challenges to understanding molecular drug resistance in P vivax are the parasite's complex biology, latency (dormant form; hypnozoites stage), culturing issues, and drug resistance indicators with a low degree of correlation with resistance associated molecular markers.The understanding of the molecular basis of treatment failure in P vivax remains elusive7Buyon LE Elsworth B Duraisingh MT The molecular basis of antimalarial drug resistance in Plasmodium vivax.Int J Parasitol Drugs Drug Resist. 2021; 16: 23-37Crossref PubMed Scopus (14) Google Scholar because putative resistance mutations are usually referred to as drug resistance indicators in the literature. Only considering these markers is insufficient for the identification of drug resistance in P vivax. Standardised in-vivo and ex-vivo assays with genomic research are essential to lay the foundation for tracking the dissemination of genotype–phenotype putative resistance mutations. Furthermore, in the era of drug resistance, monotherapies and malarial interventions are no longer sufficient to tackle genetically varied parasites with mutations. There is a need for novel treatments. There is not enough evidence to support putative resistant indicators; so, caution should be exercised when using these molecular markers to inform resistance levels or reformulate drug policy in a given geographical location.We declare no competing interests. AAK and UAA contributed equally. The COVID-19 pandemic has wreaked havoc on malaria prevention, diagnosis, and treatment, resulting in 241 million malaria cases and 627 000 malaria deaths globally in 2020, up from 14 million malaria cases in 2019, and the disruption was estimated to have contributed to 47 000 malaria deaths, two-thirds of the 2019–20 increase.1WHOWorld malaria report 2021.https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021Date: 2021Date accessed: March 30, 2022Google Scholar Malaria caused by Plasmodium vivax has the potential to affect 2·5 billion people globally, accounting for 88% of people at risk of malaria overall; however, due to its more severe course, Plasmodium falciparum receives the most attention.2Howes RE Battle KE Mendis KN et al.Global epidemiology of Plasmodium vivax.Am J Trop Med Hyg. 2016; 95: 15-34Crossref PubMed Scopus (224) Google Scholar Despite the fact that P vivax has a benign malaria course, occasional occurrences of this species’ malignant pattern have been observed worldwide.3Phyo AP Dahal P Mayxay M Ashley EA Clinical impact of vivax malaria: a collection review.PLoS Med. 2022; 19e1003890Crossref PubMed Scopus (7) Google Scholar, 4Kojom Foko LP Arya A Sharma A Singh V Epidemiology and clinical outcomes of severe Plasmodium vivax malaria in India.J Infect. 2021; 82: 231-246Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Antimalarial drug resistance is on the rise, and its spread is one of the most serious risks to malaria control and eradication. In P vivax and P falciparum, resistance to antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, and atovaquone has already been established.5Tseha ST Plasmodium species and drug resistance. IntechOpen, London2021Google Scholar Antimalarial drug resistance mechanisms and key molecular markers in P falciparum have been well described in vitro and in vivo; nevertheless, these mechanisms are difficult to assess in P vivax due to the absence of a cultivation system for this species.6Asih PBS Syafruddin D Plasmodium vivax and Drug Resistance.in: Tyagi RK Plasmodium species and drug resistance. IntechOpen, London2021https://doi.org/10.5772/intechopen.97320Date: 2021Crossref Google Scholar The search for antimalarial resistance in P vivax has centred on P falciparum orthologous genes (multidrug resistance, chloroquine resistance transporter, dihydropteroate synthase, and dihydrofolate reductase) being strongly (though not completely) associated to ex-vivo resistance assay outputs and in-vivo treatment failure.7Buyon LE Elsworth B Duraisingh MT The molecular basis of antimalarial drug resistance in Plasmodium vivax.Int J Parasitol Drugs Drug Resist. 2021; 16: 23-37Crossref PubMed Scopus (14) Google Scholar P vivax does not have a reliable genetic marker for drug resistance, probably because the drug resistance phenotype is reliant on multiple convergent molecular processes for the same outcome. It is necessary to narrow down the number of polymorphisms to be able to validate resistance markers to a drug sensitivity phenotype. Unfortunately, attempts to prove genotypic resistance have failed so far due to a unavailability of continuous culturing in P vivax, which is essential to achieve a measurable, accurate phenotypic consequence. P vivax has only tentatively been associated with treatment failure despite a quantitative increase in gene expression. Consequently, there are not any clear guidelines for determining whether in-vitro responses are sensitive or resistant to antimalarials.8Ferreira MU Nobrega de Sousa T Rangel GW et al.Monitoring Plasmodium vivax resistance to antimalarials: persisting challenges and future directions.Int J Parasitol Drugs Drug Resist. 2021; 15: 9-24Crossref PubMed Scopus (13) Google Scholar Although molecular approaches are not the most efficient means to monitor P vivax treatment susceptibility, they might be a good starting point. Herein, retrospective research on mutations of well-characterised molecular markers subject to prolonged antimalarial drug pressure is possible. The most difficult challenges to understanding molecular drug resistance in P vivax are the parasite's complex biology, latency (dormant form; hypnozoites stage), culturing issues, and drug resistance indicators with a low degree of correlation with resistance associated molecular markers. The understanding of the molecular basis of treatment failure in P vivax remains elusive7Buyon LE Elsworth B Duraisingh MT The molecular basis of antimalarial drug resistance in Plasmodium vivax.Int J Parasitol Drugs Drug Resist. 2021; 16: 23-37Crossref PubMed Scopus (14) Google Scholar because putative resistance mutations are usually referred to as drug resistance indicators in the literature. Only considering these markers is insufficient for the identification of drug resistance in P vivax. Standardised in-vivo and ex-vivo assays with genomic research are essential to lay the foundation for tracking the dissemination of genotype–phenotype putative resistance mutations. Furthermore, in the era of drug resistance, monotherapies and malarial interventions are no longer sufficient to tackle genetically varied parasites with mutations. There is a need for novel treatments. There is not enough evidence to support putative resistant indicators; so, caution should be exercised when using these molecular markers to inform resistance levels or reformulate drug policy in a given geographical location. We declare no competing interests. AAK and UAA contributed equally.